Abstract

Long-acting injections (LAIs) of antipsychotic drugs were developed over 40
years ago in an attempt to improve the long-term treatment of
schizophrenia.

Aims

To review existing guidelines concerning antipsychotic use generally, and
LAIs in particular, and how patients might be identified as potential
candidates for LAI treatment.

Method

Literature review.

Results

Currently several first-generation and one second-generation antipsychotic
LAIs are available, with others under development. Although the use of LAIs is
widespread around the world, patterns of use vary widely. Important
considerations regarding the use of LAIs include the indications for long-term
pharmacotherapy in schizophrenia in general, the indications for LAIs, the
risks associated with LAIs, the need to update guidelines and the issue of
cost.

Conclusions

The use of these injections in first-episode psychosis and
treatment-refractory schizophrenia is not currently a focus of
recommendations, but should be considered. Long-acting injections remain an
underutilised option in many countries despite frequent non-adherence with
oral medication and subsequent relapse.

Antipsychotic long-acting injections (LAIs) were introduced in 1966 in an
attempt to improve the long-term treatment of schizophrenia. We have
previously participated in the development of guidelines for the use of
injectable antipsychotic
agents.1 Although
LAIs are widely prescribed around the world, there remains concern that there
may be patients who might benefit from such formulations who do not currently
receive an appropriate trial. With the introduction of a long-acting
injectable formulation of risperidone, and the likely availability of LAI
forms of olanzapine and paliperidone in the near future, there are more
choices available to clinicians and patients. In this article we review the
existing guidelines for the use of LAIs in schizophrenia and discuss how
further perspectives have evolved over the decade since their publication.
Important considerations include the indications for long-term pharmacotherapy
in schizophrenia in general, the indications for LAIs, the issue of cost, the
potential use of LAIs in first-episode or early-phase illness and the
potential role of LAIs in treatment-refractory disorder.

Need for long-term treatment of schizophrenia

As more and more studies have been conducted over the past several decades,
controversy regarding the indications and contraindications for antipsychotics
in general has diminished. It is widely accepted that antipsychotic
medications are indicated for both short-term and long-term treatment of
schizophrenia, regardless of the subtype, patient age, type of onset or
presence of comorbid psychiatric conditions. There is, however, less unanimity
regarding the appropriate duration of treatment, particularly for individuals
who have experienced only one episode of illness (see
Table 1).

Guidelines for the duration of treatment following single-episode and
multi-episode schizophrenia

It was not until the 1980s that placebo-controlled trials of maintenance
treatment following a single episode were first
conducted.2,3
These studies were generally of relatively short duration (1–2 years),
given the potential and expected duration of a schizophrenic
illness.4 Although
these trials, coupled with more naturalistic assessment of relapse
prevention,5 support
the superiority of continued antipsychotic medication in comparison with
placebo or no treatment, the relapse rates even on placebo were generally
substantially lower than those observed under placebo treatment following
multiple episodes of illness. This observation suggested that a substantial
subgroup of people with first-episode disorder are not at risk of relapse when
medications are discontinued for a year or more, and called into question the
relative necessity, or benefit-to-risk ratio, of long-term treatment following
a single episode. For example, Robinson et al reported that 18% of
patients followed for up to 5 years after symptomatic recovery from their
first episode had not experienced a second
episode.5 However,
at the same time these investigators reported a five times higher relapse rate
among those who discontinued medication compared with those who continued.
Kane et al reported a 40% relapse rate on placebo after 1 year in
comparison with none on active
medication.2 These
data suggest that a minority might not need medication to prevent relapse, but
we have as yet no way of identifying such patients. The data from long-term
follow-up studies also emphasise the potential heterogeneity of outcome in
schizophrenia, with or without
medication.6,7
It is important to recognise that long-term exposure to medications is
generally not without risk. Concerns regarding the development of tardive
dyskinesia,8 and
more recently endocrine and metabolic adverse
effects,9 have also
influenced the benefit-to-risk ratio of long-term treatments.

A further complication in considering the indications for long-term
pharmacotherapy in the management of schizophrenia involves the nature of the
illness itself and its potential impact on cognitive functioning, insight,
propensity to suicide or violent behaviour and comorbid substance misuse, as
well as social and vocational functioning. An illness in which an exacerbation
can be associated with loss of insight and diminished interest in taking
medication, as well as potential dangerousness to self and others, poses a
somewhat different set of challenges from those associated with less
complicated changes in health status. In essence, schizophrenia is a complex
condition and the majority of patients need longer-term treatment because
relapse is associated with significant personal costs (see Appendix 1).

Guidelines for treatment of schizophrenia

Table 1 provides a summary
of the various guideline recommendations regarding duration of treatment
following a single episode and those for multi-episode patients. In our view
the guidelines are either overly conservative (i.e. too short in suggested
duration) or inordinately vague in their recommendations, particularly as
applied to patients with a single episode. Although placebo-controlled trials
of maintenance treatment following a first episode have not lasted more than 2
years, there are prospective longitudinal studies that provide a valuable
perspective. Robinson et al reported on a large cohort of patients
with a first psychotic episode, and after 5 years of follow-up the single most
powerful predictor of relapse was medication
non-adherence.5 The
relapse rate was five times higher among those who discontinued. That was true
for the second as well as the first relapse. These and other data provide
strong support for longer duration of treatment following a first episode. It
is also important to consider the potential impact of a relapse on an
individual at this phase of illness. Most patients who are appropriately
treated following the onset of a first schizophrenic episode can be expected
to have a good response to treatment, with the overwhelming majority achieving
symptomatic remission within 6–12
months.4 It is
ironic that individuals who are doing the best might also have the most to
lose if they experience a relapse. Additionally, this is occurring in the
context of the patient's (and family's) frequent difficulty accepting the
reality of the illness and the potential hesitancy or ambivalence on the part
of the clinical team to make strong recommendations (or even a definitive
diagnosis).

Guidelines regarding the use of long-acting injections

Excerpts from five guidelines on the treatment of schizophrenia addressing
the use of antipsychotic LAIs are given in Appendix
2.10–16
The guidelines are similar in their focus on patients who have demonstrated
non-adherence or recurrent relapses related to partial or full non-adherence.
They also highlight the importance of patient preference. The National
Institute for Health and Clinical Excellence (NICE) guidelines suggest the
possibility of a treatment plan in which the avoidance of covert non-adherence
to the antipsychotic regimen is a
priority,11 but in
general the guidelines emphasise the use of LAIs after non-adherence has
already been demonstrated and has been linked to repeated relapse.

Who is an appropriate patient for antipsychotic LAIs?

Given the nature of the schizophrenic illness, the frequency and
consequences of psychotic relapse and the high rates of non-adherence in
medication-taking, it seems responsible to consider injectable antipsychotics
as a potential strategy for many patients. There are individuals for whom a
decision not to consider LAIs may be appropriate. The first is the patient who
has consistently demonstrated his or her ability to take oral medication and
chooses to continue doing so. The second is the individual who despite
adequate discussion of potential benefits and risks, and sufficient
psychoeducation regarding the nature of the illness, adamantly refuses even to
try a long-acting formulation. The third is the patient unable to tolerate or
unresponsive to the medications available in long-acting injectable
formulations.

Adherence

Clinical context

The majority of patients with schizophrenia who are readmitted to hospital
have exhibited some degree of non-adherence, and often it is unclear whether
non-adherence preceded the relapse or was a consequence of
it.17 The use of
LAIs would allow clinicians to be certain whether a relapse occurred because
of non-adherence or despite adequate medication. Clearly, this has important
implications for subsequent treatment planning regarding the potential need to
alter the dosage, the medication and the psychosocial treatment. When patients
are receiving LAIs there is certainty as to a critical ingredient in the
management of the illness. If a patient misses an injection there is immediate
awareness on the part of the clinical team that an intervention is necessary,
and yet there is also some time to act before a crisis is likely to ensue.

Comorbid substance misuse

Substance misuse strongly predicts medication
non-adherence.17,18
In cases of comorbid substance misuse the knowledge that the antipsychotic
medication has definitely been taken, in the form of an LAI, is important in
determining the cause of potential subsequent relapse.

Psychosocial consequences

Family relationships often suffer when uncertainty and anxiety associated
with the potential for and the consequences of non-adherence weigh heavily on
interactions. Many relatives and carers are directly involved in oral
medication administration. Since they often face the initial burden (and even
physical threat and danger) associated with a psychotic relapse, they are
particularly sensitive to the issue of adherence. The use of LAI medication
can provide enormous relief from this concern and facilitate the normalisation
of family interactions.

Inability to accurately predict non-adherence

There are numerous reports evaluating the predictors and risk factors for
non-adherence that have been assessed, but despite these efforts physicians in
routine clinical practice are most often neither able to predict which
patients are at risk nor able to identify which patients are actually failing
to adhere to their medication regimen. Studies indicate that both patients and
clinicians overestimate the degree of
adherence.19,20
Therefore, we have to ask ourselves, given the availability of strategies to
guarantee the potential benefits of continuous medication, why would we not
avail ourselves and our patients of that potential advantage? In other words,
what are the barriers to LAI prescribing?

Research contexts

There are a number of research contexts where certainty regarding
adherence, by administering medication in the form of an LAI, enables the
investigators to draw more valid conclusions about the research question
posed. Examples include issues such as establishing the minimum effective dose
for the prevention of
relapse,21,22
evaluating the impact of family therapy on treatment
outcome,23 and
establishing the incidence and dosage-related risk of tardive
dyskinesia.8 In all
of these studies it would have been enormously difficult to draw meaningful
conclusions without reasonable certainty that the participating patients were
actually ingesting the prescribed dose of medication on a consistent
basis.

Key concerns

Clinician and patient attitudes

Many clinicians are hesitant to use LAIs, for reasons discussed by, for
example, Waddell &
Taylor.24 Can and
should these attitudes be changed? Should physicians be more proactive in
offering this option to patients, providing an evidence-based rationale,
addressing concerns and the natural reluctance to receive injections in an
appropriate, patient-oriented, shared decision-making fashion? Many guidelines
suggest that the use of LAI formulations be considered when patients express a
preference for them. This has always seemed to have a rather unfortunate or
unintended implication. Do we really expect patients to readily express a
preference for receiving medications by injection? This seems unlikely and it
appears to put too much onus on patient preference. Given a preference,
patients would prefer not to be ill in the first place. Certainly the use of
LAI medication should (in all but legally influenced situations) be consistent
with patient preference. However, the role of the clinical team, the family
and the health delivery system in providing the evidence, the education, the
support, the convenience and the financing is not irrelevant in determining
patient preference. The discussion and shared decision-making around the use
of long-acting medication should be part of an active engagement in working
towards shared goals of recovery and
wellness,25 not a
single factor unnecessarily loaded with various misinformation, bias,
avoidance of extra effort and so on, which can easily be ignored or dismissed
under the rubric of `patient preference'.

Are people with first-episode psychosis candidates for LAIs?

The guidelines and general practice tend to reserve LAI drugs for patients
who have already experienced significant sequelae of non-adherence, e.g.
relapse and often rehospitalisation. There is no published head-to-head
comparison of outcomes among first-episode patients receiving LAI drugs and
those receiving oral medication. However, non-adherence is a considerable
problem in first-episode patients. Many such individuals have not fully
accepted the reality of their illness, and since remission of symptoms is
common after treatment of a first episode, there is often a false sense of not
needing continued medication. In addition, many clinicians assume that
patients at this phase of illness would be unlikely to accept LAI medication.
There have been two recent studies, however, that challenge this assumption.
Emsley et al reported on 60 first-episode patients who were eligible
for a study of risperidone
LAI.26 Only 9 (15%)
refused. Patients were followed for up to 2 years; 72% completed the 2-year
trial. Weiden et al reported on a two-stage model of engagement and
then randomisation to treatment with either LAI medication or oral
drugs.27
Seventy-four patients with a first episode of psychosis consented to an
assessment protocol; 46 patients who met diagnostic criteria for a
schizophrenia, schizoaffective or schizophreniform disorder and had had less
than 16 weeks of antipsychotic treatment were asked to participate in a
randomised controlled trial. Eighty-three per cent of eligible patients
consented to participate, and 73% of those who were randomised to LAIs
accepted them. Only 12-week follow-up data have been reported, and attitudes
towards medication, assessed by masked raters, revealed no significant
difference between treatment groups. Medication adherence, on the other hand,
was significantly better in the group receiving injections. These studies
suggest that the use of LAI medication is feasible in first-episode disorder
and may have distinct advantages. Clearly, further research is warranted. A
critical question that needs to be addressed is whether or not LAIs can be
effective in reducing the risk of nonadherence in people with first-episode
illness who, in general, have a high likelihood of becoming nonadherent but
have yet to manifest such behaviour.

Treatment-resistant schizophrenia

There has been remarkably little research addressing the role of LAI drugs
in patients with treatment-resistant disorder. It is not really known to what
extent non-adherence contributes to the evolution or current manifestation of
treatment resistance. For example, few clinicians obtain a drug blood level
before considering a patient to be treatment-resistant. It is also possible
that repeated exacerbations and relapses due to poor adherence contribute to
the evolution of treatment resistance, but this too has not been well studied.
Some individuals might experience low bioavailability or rapid metabolism and
this could contribute to apparent treatment resistance. These potential
factors suggest that a trial of LAI medication would be justified, but this
not a well-established practice. Ideally, true treatment resistance should be
differentiated from the `pseudo' treatment resistance associated with
non-adherence or inadequate blood levels. Certainly research in this area is
sorely needed.

Key questions and considerations

How far have we come in the 10 years since we published guidelines on
the use of LAIs?

It appears that in some countries utilisation of LAIs has increased, but in
most there has not been a major change despite the introduction of the first
long-acting atypical antipsychotics. Statements have been provided on the
indications for LAIs from widely disseminated guidelines on the pharmacologic
treatment of schizophrenia, and although we believe that these guidelines are
generally too conservative in their recommendations, even these guidelines are
infrequently followed.

Who should be considered for depot drugs?

Any patient for whom long-term treatment is indicated should be considered
a candidate for LAI. Patients who are irregular in taking medications are
particularly appropriate candidates given the well-established relationship
between non-adherence and risk of relapse. Even if patients initially refuse
this option, clinicians should work with them (through the therapeutic
alliance) to help them understand the potential advantages.

When should the treatment start?

Treatment should start as soon as possible after the improvement of acute
symptoms (oral, or short- or intermediate-acting intramuscular medication is
preferable for acute treatment as long as flexibility of dosage is
desirable).

Which drugs?

In choosing a drug the clinician should consider previous experience,
personal patient preference, patient's history of response (both therapeutic
and adverse effects) and pharmacokinetic properties. There is no definite
evidence that any one LAI is superior to another in terms of efficacy,
although they may differ in side-effect profile. With the development of
additional LAIs more data are available on the effectiveness of these drugs,
but unfortunately there are still relatively few well-designed, head-to-head,
long-term comparisons of LAIs and oral medications in the prevention of
relapse and rehospitalisation.

Need for additional research

There are a number of areas where additional research is necessary. There
are still too few large-scale, long-term trials assessing the impact of LAIs
on outcome. Care needs to be taken to understand the trade-off between
naturalistic and controlled trials, as well as between efficacy and
effectiveness trials. More research is needed on the potential role of LAIs in
patients with a first episode of psychosis, treatment-refractory schizophrenia
or comorbid substance misuse.

Conclusion

The overall recommendations from the 1998 guidelines remain as appropriate
today as they were 10 years
ago.1 Long-acting
injections can be a valuable tool in managing schizophrenia and facilitating
optimum outcome. Perhaps more data are necessary to develop a broader
consensus; however, physician and patient biases and reluctance remain
important targets for guidance, psychoeducation and shared decision-making.
Given the personal suffering, family burden and societal costs associated with
non-adherence and consequent relapse, in our opinion the potential value of
LAI medication continues to be inadequately appreciated.

Appendix 1

Case vignette 1

R.K. was a 20-year-old college student when he experienced his first
episode of schizophrenia. He left school and was admitted to hospital near his
home. He was treated in the hospital for 4 weeks and then in an out-patient
clinic for 6 months. He found a job as an office assistant in an advertising
agency through a friend of his father. Eight months following his discharge
from the hospital he returned to school to restart his sophomore year in
college. At that point he was convinced that he had fully recovered and no
longer needed medication. Seven months later he was again admitted to
hospital. He never returned to college on a full-time basis, but did try
subsequently to take night courses at a community college near his home.

Although we cannot be certain as to the outcome if R.K. had continued with
his medication, it certainly would have significantly reduced the risk of a
second episode. At this stage of illness one or two relapses can have a major
impact in diminishing one's academic, vocational and social opportunities.

Case vignette 2

K.L. experienced the onset of schizophrenia at the age of 23 years. He was
initially hospitalised for 2 months and responded well to antipsychotic
medication. Within 4 months of discharge he withdrew from out-patient
treatment and discontinued medication. He was readmitted to hospital 5 months
later. After 3 weeks in the hospital he was again referred for out-patient
treatment. His attendance was sporadic and again he discontinued medication
within a few months. After this pattern repeated itself yet again the
in-patient staff suggested the possibility of long-acting injection
medication.

This case illustrates an all-too-common pattern of hospitalisation,
non-adherence and rehospitalisation which often occurs several times before
the use of LAI is considered. In some such cases it is never considered.

Appendix 2

Excerpts from guidelines

`Depot preparations should be offered as a treatment option where a service
user expresses a preference for such treatment because of its convenience or
as part of a treatment plan in which avoidance of covert nonadherence to the
antipsychotic regimen is a clinical priority.' (NICE Guidelines,
2002)11

`Consider long-acting injection antipsychotic medication for patients with
recurrent relapses related to partial or full nonadherence. The oral form of
the same medication (e.g. fluphenazine, haloperidol and risperidone) is the
logical choice for initial treatment.' (American Psychiatric Association
Guidelines,
2004)12

`Long-acting injection antipsychotic medication maintenance treatment
should be available and considered for persons who have a history of frequent
relapse on oral medication, or a history of problems with adherence on oral
medication, or who prefer the long-acting injection depot regimen.' (PORT
Recommendations,
2003)10

`The Texas Medication Algorithm recommends considering the use of LAIs when
schizophrenic patients are inadequately adherent at any
stage.'15,16

American Diabetes Association, American Psychiatric Association,
American Association of Clinical Endocrinologists, North American Association
for the Study of Obesity. Consensus Development Conference on Antipsychotic
Drugs and Obesity and Diabetes. J Clin Psychiatry2004
; 65: 267
-73.